Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4
Abstract Background Thiamine metabolism dysfunction syndrome 4 (THMD4, OMIM #613710) is an autosomal recessive inherited disease caused by the deficiency of SLC25A19 that encodes the mitochondrial thiamine pyrophosphate (TPP) transporter. This disorder is characterized by bilateral striatal degradat...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-09-01
|
| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13023-021-02028-4 |
| id |
doaj-461027c381034d498687e1811b6ce7b3 |
|---|---|
| record_format |
Article |
| spelling |
doaj-461027c381034d498687e1811b6ce7b32021-10-03T11:37:33ZengBMCOrphanet Journal of Rare Diseases1750-11722021-09-0116111010.1186/s13023-021-02028-4Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4Yuanying Chen0Boliang Fang1Xuyun Hu2Ruolan Guo3Jun Guo4Kenan Fang5Jingwen Ni6Wei Li7Suyun Qian8Chanjuan Hao9Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthPediatric Intensive Care Unit, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthBeijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthBeijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthBeijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthPediatric Intensive Care Unit, Luoyang Maternal and Child Health HospitalPediatric Intensive Care Unit, Luoyang Maternal and Child Health HospitalBeijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthPediatric Intensive Care Unit, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthBeijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthAbstract Background Thiamine metabolism dysfunction syndrome 4 (THMD4, OMIM #613710) is an autosomal recessive inherited disease caused by the deficiency of SLC25A19 that encodes the mitochondrial thiamine pyrophosphate (TPP) transporter. This disorder is characterized by bilateral striatal degradation and progressive polyneuropathy with the onset of fever of unknown origin. The limited number of reported cases and lack of functional annotation of related gene variants continue to limit diagnosis. Results We report three cases of encephalopathy from two unrelated pedigrees with basal ganglia signal changes after fever of unknown origin. To distinguish this from other types of encephalopathy, such as acute necrotizing encephalopathy, exome sequencing was performed, and four novel heterozygous variations, namely, c.169G>A (p.Ala57Thr), c.383C>T (p.Ala128Val), c.76G>A (p.Gly26Arg), and c.745T>A (p.Phe249Ile), were identified in SLC25A19. All variants were confirmed using Sanger sequencing. To determine the pathogenicity of these variants, functional studies were performed. We found that mitochondrial TPP levels were significantly decreased in the presence of SLC25A19 variants, indicating that TPP transport activities of mutated SLC25A19 proteins were impaired. Thus, combining clinical phenotype, genetic analysis, and functional studies, these variants were deemed as likely pathogenic. Conclusions Exome sequencing analysis enables molecular diagnosis as well as provides potential etiology. Further studies will enable the elucidation of SLC25A19 protein function. Our investigation supplied key molecular evidence for the precise diagnosis of and clinical decision-making for a rare disease.https://doi.org/10.1186/s13023-021-02028-4SLC25A19Thiamine pyrophosphateThiamine metabolism dysfunction syndrome 4Functional studyExome sequencingCompound heterozygosity |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Yuanying Chen Boliang Fang Xuyun Hu Ruolan Guo Jun Guo Kenan Fang Jingwen Ni Wei Li Suyun Qian Chanjuan Hao |
| spellingShingle |
Yuanying Chen Boliang Fang Xuyun Hu Ruolan Guo Jun Guo Kenan Fang Jingwen Ni Wei Li Suyun Qian Chanjuan Hao Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4 Orphanet Journal of Rare Diseases SLC25A19 Thiamine pyrophosphate Thiamine metabolism dysfunction syndrome 4 Functional study Exome sequencing Compound heterozygosity |
| author_facet |
Yuanying Chen Boliang Fang Xuyun Hu Ruolan Guo Jun Guo Kenan Fang Jingwen Ni Wei Li Suyun Qian Chanjuan Hao |
| author_sort |
Yuanying Chen |
| title |
Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4 |
| title_short |
Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4 |
| title_full |
Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4 |
| title_fullStr |
Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4 |
| title_full_unstemmed |
Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4 |
| title_sort |
identification and functional analysis of novel slc25a19 variants causing thiamine metabolism dysfunction syndrome 4 |
| publisher |
BMC |
| series |
Orphanet Journal of Rare Diseases |
| issn |
1750-1172 |
| publishDate |
2021-09-01 |
| description |
Abstract Background Thiamine metabolism dysfunction syndrome 4 (THMD4, OMIM #613710) is an autosomal recessive inherited disease caused by the deficiency of SLC25A19 that encodes the mitochondrial thiamine pyrophosphate (TPP) transporter. This disorder is characterized by bilateral striatal degradation and progressive polyneuropathy with the onset of fever of unknown origin. The limited number of reported cases and lack of functional annotation of related gene variants continue to limit diagnosis. Results We report three cases of encephalopathy from two unrelated pedigrees with basal ganglia signal changes after fever of unknown origin. To distinguish this from other types of encephalopathy, such as acute necrotizing encephalopathy, exome sequencing was performed, and four novel heterozygous variations, namely, c.169G>A (p.Ala57Thr), c.383C>T (p.Ala128Val), c.76G>A (p.Gly26Arg), and c.745T>A (p.Phe249Ile), were identified in SLC25A19. All variants were confirmed using Sanger sequencing. To determine the pathogenicity of these variants, functional studies were performed. We found that mitochondrial TPP levels were significantly decreased in the presence of SLC25A19 variants, indicating that TPP transport activities of mutated SLC25A19 proteins were impaired. Thus, combining clinical phenotype, genetic analysis, and functional studies, these variants were deemed as likely pathogenic. Conclusions Exome sequencing analysis enables molecular diagnosis as well as provides potential etiology. Further studies will enable the elucidation of SLC25A19 protein function. Our investigation supplied key molecular evidence for the precise diagnosis of and clinical decision-making for a rare disease. |
| topic |
SLC25A19 Thiamine pyrophosphate Thiamine metabolism dysfunction syndrome 4 Functional study Exome sequencing Compound heterozygosity |
| url |
https://doi.org/10.1186/s13023-021-02028-4 |
| work_keys_str_mv |
AT yuanyingchen identificationandfunctionalanalysisofnovelslc25a19variantscausingthiaminemetabolismdysfunctionsyndrome4 AT boliangfang identificationandfunctionalanalysisofnovelslc25a19variantscausingthiaminemetabolismdysfunctionsyndrome4 AT xuyunhu identificationandfunctionalanalysisofnovelslc25a19variantscausingthiaminemetabolismdysfunctionsyndrome4 AT ruolanguo identificationandfunctionalanalysisofnovelslc25a19variantscausingthiaminemetabolismdysfunctionsyndrome4 AT junguo identificationandfunctionalanalysisofnovelslc25a19variantscausingthiaminemetabolismdysfunctionsyndrome4 AT kenanfang identificationandfunctionalanalysisofnovelslc25a19variantscausingthiaminemetabolismdysfunctionsyndrome4 AT jingwenni identificationandfunctionalanalysisofnovelslc25a19variantscausingthiaminemetabolismdysfunctionsyndrome4 AT weili identificationandfunctionalanalysisofnovelslc25a19variantscausingthiaminemetabolismdysfunctionsyndrome4 AT suyunqian identificationandfunctionalanalysisofnovelslc25a19variantscausingthiaminemetabolismdysfunctionsyndrome4 AT chanjuanhao identificationandfunctionalanalysisofnovelslc25a19variantscausingthiaminemetabolismdysfunctionsyndrome4 |
| _version_ |
1716845341693706240 |